Novel Antibacterial Scaffold from Natural Products

来自天然产物的新型抗菌支架

基本信息

批准号：
8298158
负责人：
Esteban Edward Mena
金额：
$ 28.78万
依托单位：
LIFEPHARMS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8298158
关键词：
Acute Acute Toxicity Tests Adverse effects Affinity Agaricales Anti-Bacterial Agents Antibiotic Resistance Antibiotics Ascomycota Awareness Bacteria Bacterial Antibiotic Resistance Basidiomycota Biological Biological Assay Biological Factors Cessation of life Chemical Structure Chemicals Chemistry Clinical Collaborations Collection Communicable Diseases Community Hospitals Data Development Drug resistance Enterococcus Epidermis Evaluation Exhibits Fruit Genus staphylococcus Goals Grant Health Care Costs In Vitro Infection Inhibitory Concentration 50 Laboratories Lead Libraries Liver Microsomes Mammalian Cell Measures Metabolic Metabolic Biotransformation Metabolism Methicillin Resistance Methodology Modification Mus Organism Pathway interactions Permeability Pharmaceutical Preparations Pharmacologic Substance Phase Preparation Prevalence Process Property Protein Isoforms Relative (related person)Research Resistance Screening procedure Series Serum Small Business Innovation Research Grant Source Specific qualifier value Structure-Activity Relationship Testing Therapeutic Agents Toxic effect United States Vancomycin resistant enterococcus analog antimicrobial bactericide combat cytotoxic cytotoxicity design drug candidate drug development fighting improved in vitro Assay in vivo inhibitor/antagonist innovation interest meetings methicillin resistant Staphylococcus aureus novel pathogen pre-clinical programs research study resistance mechanism scaffold

项目摘要

DESCRIPTION (provided by applicant): Despite the rise of bacterial resistance to antibiotics, the development of new antibiotics is on the decline. Methicillin-resistant Staphococcal aureus infections (MRSA) in the United States has been increasing, causing 19,000 deaths per year in the United States and contributing to $3 billion to $4 billion of additional annual health care costs. The issue of combating resistance has been exacerbated by the relative scarcity of new chemical scaffolds discovered or developed. Most of the antibacterial research at pharmaceutical companies has been towards developing analogs of existing drugs through traditional chemistry driven SAR programs. Very few new classes of antibiotics have been introduced in the past decades, and most antibiotics act on familiar targets. In addition, even though natural products have been a rich source of new antibacterials, many pharmaceutical companies have natural product libraries that have been thoroughly screened and offer little in the way of diversity or novelty. There is a growing awareness that natural product libraries, particularly those with a fungal origin, need to exploit fungal cryptic or secret pathways that normally are not expressed in laboratory conditions. To exploit the largely undiscovered secondary metabolites of mushrooms (basidiomycetes and ascomycetes), LifePharms, Inc. has established a collection of field- collected, environmentally challenged fruiting bodies. LifePharms/Microbiotix collaboration has identified, purified, and characterized two compounds that exhibit potent antibacterial activity (MICs as low as 0.5 5g/ml) against Gram-positive pathogens, including MSSA, MRSA, MRSE, and VRE, and favorable cytotoxicity profiles (CC50 > 100 5g/ml). The chemical structures of these two lead compounds indicate they are novel antibacterial compounds. In addition, we have purified and partially characterized three more potent antibacterial compounds that will serve as alternative scaffolds. In this Phase I grant, we will i) evaluate these compounds in a series of in vitro assays that will measure ADMET, ii) chemically optimize these compounds by generating analogs using semi-synthetic methodologies to determine structure activity relationships and to improve potency and selectivity, iii) Data obtained from these assays will inform the design of subsequent analogs, resulting in an iterative process of analog design and evaluation, to improve the efficacy, selectivity, and ADMET properties of the scaffolds. In Phase II, compounds that meet the specified criteria for efficacy, selectivity, and ADMET properties will be tested for acute toxicity and antibacterial efficacy in mice.

描述（由申请人提供）：尽管细菌对抗生素的耐药性升高，但新抗生素的发展仍在下降。美国耐甲氧西林金黄色葡萄球菌感染（MRSA）一直在增加，每年在美国造成19,000例死亡，并贡献了30亿美元至40亿美元的额外卫生保健费用。被发现或开发的新化学脚手架的相对稀缺性加剧了打击抵抗力的问题。制药公司的大多数抗菌研究一直在通过传统化学驱动的SAR计划来开发现有药物的类似物。在过去的几十年中，很少引入新的抗生素类，并且大多数抗生素对熟悉的靶标作用。此外，即使天然产品一直是新抗菌药物的丰富来源，但许多制药公司的天然产品库已被彻底筛选，几乎没有多样性或新颖性的方式。人们越来越意识到，天然产品库，尤其是具有真菌起源的天然产品库，需要利用通常在实验室条件下通常不表达的真菌隐性或秘密途径。为了利用蘑菇的未发现的二级代谢物（基本菌和伴奏），Lifepharms，Inc。建立了一系列收集的现场，环境挑战的果实体。 Lifepharms/Microbiotix合作已针对革兰氏阳性病原体（包括MSSA，MRSA，MRSA，MRSE和VRE），鉴定，纯化和表征两种化合物，这些化合物表现出有效的抗菌活性（低至0.5 5G/ml），以及良好的细胞毒性谱分析（CC50> 100 5G/ml）。这两种铅化合物的化学结构表明它们是新型抗菌化合物。此外，我们已经纯化并部分表征了另外三种有效的抗菌化合物，这些抗菌化合物将用作替代脚手架。 In this Phase I grant, we will i) evaluate these compounds in a series of in vitro assays that will measure ADMET, ii) chemically optimize these compounds by generating analogs using semi-synthetic methodologies to determine structure activity relationships and to improve potency and selectivity, iii) Data obtained from these assays will inform the design of subsequent analogs, resulting in an iterative process of analog design and evaluation, to improve the efficacy,脚手架的选择性和ADMET性质。在第二阶段，将测试符合指定标准的功效，选择性和ADMET特性标准的化合物，以测试小鼠的急性毒性和抗菌功效。